Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation

神经类固醇-BZ 组合：减少滥用和镇静的策略

• 批准号: 8322247
• 负责人: JAMES K ROWLETT
• 金额: $ 60.22万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322247
• 关键词: Adverse drug effect; Adverse effects; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Anxiety Disorders; Ataxia; Aversive Stimulus; Behavior; Benzodiazepines; Brain; Characteristics; Clinical; Clonazepam; Conflict (Psychology); Data; Development; Diazepam; Dose; Drug Combinations; Effectiveness; Female; Future; Goals; Gonadal Steroid Hormones; Injection of therapeutic agent; Intravenous; Investigation; Laboratories; Luteal Phase; Macaca mulatta; Measures; Mediating; Menstrual cycle; Modeling; Modern Medicine; Monkeys; Motor; Muscle relaxants; Nature; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Posture; Pregnanolone; Procedures; Progesterone; Psychotropic Drugs; Research; Rest; Role; Schedule; Sedation procedure; Self Administration; Sleep; Sleep Disorders; Testing; Therapeutic Index; base; ganaxolone; hypnotic; improved; neurosteroids; novel; novel strategies; pre-clinical; programs; receptor; sedative; sex

DESCRIPTION (provided by applicant): Benzodiazepines (BZs) are prescribed widely as anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. Although BZs are among the safest psychoactive drugs in modern medicine, their utility is often limited by unwanted side effects such as abuse liability and sedative-motor effects. The overall goal of this application is to determine quantitatively the extent to which combining a BZ with another type of GABAA modulator, a neuroactive steroid, results in enhanced anxiolytic-like effects but not enhanced unwanted side-effects. Specific Aim 1 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will enhance the anxiolytic-like effects of BZ-type drugs in a supra-additive manner. Conventional BZs produce characteristic increases in operant behavior that are suppressed by aversive stimuli, i.e., induce "anti-conflict" effects. Using a rhesus monkey conflict procedure, we will evaluate the anxiolytic-like effects of conventional BZs (e.g., clonazepam), alone or in combination with neuroactive steroids (e.g., ganaxolone, pregnanolone). Specific Aim 2 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will alter the self-administration of BZ-type drugs in an infra-additive manner. These studies will employ a progressive-ratio (PR) schedule of intravenous drug injection to examine the reinforcing effectiveness of BZs, either alone or in combination with neuroactive steroids. Specific Aim 3 will initiate investigation of the combined effects of neuroactive steroid and BZ-type drugs in a novel observation procedure that distinguishes different levels of sedation and motor function. We will use observational procedures recently developed in our laboratory that dissociate ataxia-like effects, sleep/rest-associated postures, moderate and deep sedation. In all studies, mechanism of action will be assessed by testing receptor subtype-specific GABAA compounds. All combination data will be evaluated with isobolographic/dose-addition analysis in order to determine if effects of drug combinations are additive, supra-additive, or infra-additive. Finally, we will conduct targeted studies with female monkeys to begin to investigate the role of the menstrual cycle in mediating the sedative-motor effects of BZs, based on the observation that endogenous neuroactive steroid levels increase with the progesterone surge during the luteal phase. This pilot study should provide a springboard for evaluating sex as a factor in BZ and neuroactive steroid pharmacology in future applications. The ultimate goal for this research program is to provide critical preclinical information for development of a broadly effective combination product with an improved side effect profile for treating anxiety disorders. PUBLIC HEALTH RELEVANCE: Benzodiazepines (i.e., Valium-like drugs) are remarkably effective in treating anxiety and sleep disorders, but a major problem with these drugs are side effects, including significant abuse liability. In fact, the abuse of benzodiazepines appears to be on the rise in the US, making the need for improving the side effect profile of these drugs a clear priority. Our research program will examine a novel approach to reducing benzodiazepine abuse: We are exploring a novel combination product, consisting of a benzodiazepine and another type of drug referred to as a "neuroactive steroid" that in preliminary studies showed enhanced anxiety-reducing effects and virtually no enhancement of abuse potential.

描述（由申请人提供）：苯二氮卓类药物（BZ）被广泛规定为抗焦虑药，催眠药，肌肉松弛剂和抗惊厥药。尽管BZ是现代医学中最安全的精神活性药物之一，但它们的效用通常受到不必要的副作用（例如滥用责任和镇静运动影响）的限制。该应用程序的总体目标是 为了定量确定将BZ与另一种类型的GABAA调节剂（一种神经活性类固醇）结合的程度，会导致抗焦虑样效应增强，但没有增强不良的副作用。具体目标1将评估以下假设：在GABAA受体上起作用的神经活性类固醇将以超添加的方式增强BZ型药物的抗焦虑样作用。常规的BZ会导致操作行为的特征增加，这些行为被厌恶刺激抑制，即诱导“反冲突”效应。使用恒河猴冲突程序，我们将单独或与神经活性类固醇（例如Ganaxolone，dimenanolone）单独或与传统BZ（例如氯硝西am）的抗焦虑样作用进行评估。具体目标2将评估以下假设：在GABAA受体上起作用的神经活性类固醇将以侵入性的方式改变BZ型药物的自我给药。这些研究将采用静脉注射药物注射的进行性比率（PR）时间表来检查BZ的增强有效性，无论是单独还是与神经活性类固醇结合使用。具体目标3将在一种新的观察程序中研究神经活性类固醇和BZ型药物的综合作用，该方法区分了不同水平的镇静和运动功能。我们将使用最近在实验室中开发的观察过程，这些程序分离出类似共济失调的效果，睡眠/休息相关的姿势，中度和深层镇静。在所有研究中，将通过测试受体亚型特异性GABAA化合物来评估作用机理。所有组合数据都将通过同型/剂量 - 添加分析进行评估，以确定药物组合的影响是加性，超添加性或红外添加性的。最后，我们将与雌猴进行有针对性的研究以开始 基于观察到，在黄体期内内源性神经运动类固醇水平随孕酮的刺激而增加，因此研究月经周期在介导BZ的镇静运动作用中的作用。这项试验研究应为在未来应用中评估性别作为BZ和神经活性类固醇药理学的因素提供一个跳板。该研究计划的最终目标是提供关键的临床前信息，以开发广泛有效的组合产品，并改善了治疗焦虑症的副作用。 公共卫生相关性：苯二氮卓类药物（即，类似Valium的药物）在治疗焦虑和睡眠障碍方面非常有效，但是这些药物的一个主要问题是副作用，包括重大滥用责任。实际上，滥用苯二氮卓类药物似乎是 在美国的崛起中，需要清楚地改善这些药物的副作用概况 优先事项。我们的研究计划将研究一种新的减少苯二氮卓类药物滥用的方法：我们正在探索一种新型的组合产品，该产品由苯二氮卓类和另一种类型的药物组成，被称为“神经活性类固醇”，在初步研究中，该研究表明，焦虑症状降低效果增强，实际上没有增强滥用潜力的增强。